A study of mechanisms by which teratogenic drugs or mutant genes produce limb deformities is proposed. The drugs such as vitamin A (retinoic acid), cytosine arabinoside, 5-fluorodeoxyuridine, ribavirin, DON (6-diazo-5-oxonorleucine), and proline analogs are selected because they show some specificity in the production of stage-dependent limb deformities in mouse embryos. The mouse mutants to be employed are cmd (cartilage matrix deficiency), hx (hemimelia extra toe) and pc (phocomelic), which are selected for the same reason. We aim to determine: early changes in the pattern of cell proliferation, deviations of cell death in normal and ectopic sites, alterations in the properties of cell aggregation, and alterations in molecular events related to chondrogenic differentiation. Whole embryos labeled in utero or in vitro with 3H-thymidine followed by radioautography and radiochemical procedures will be used in studies on changes in the pattern of DNA synthesis and cell proliferation. In investigations on changes in cell surfaces during normal and abnormal development, we will use plant lectins (radio-labeled or fluorescein-conjugated) in suspensions of cells derived from limb mesenchyme. Organ cultures of limb buds, derived from normal and abnormal embryos or exposed directly to teratogenic chemicals, will be used in studies on chondrogenesis. Electron microscopy in conjunction with stains specific for matrix components, immunohistology, and radioactive precursors will be employed in studies on collagen and proteoglycan synthesis and in probing structural changes in the extracellular matrix of cartilage. Appropriate parallel studies of teratogen-treated and mutant embryos will be conducted.